THIS INVENTION relates generally to mood disorders. In particular, the present invention is concerned with a method and apparatus for diagnosis of a mood disorder, particularly unipolar and/or bipolar mood disorder, or predisposition therefor. The invention also relates to a process of using the diagnostic method to prevent mood disorders, to identify therapeutic compounds for alleviation of mood disorders, and to identify genetic markers associated with such disorders.
A variety of mood disorders exist which compromise to varying degrees the social integration and quality of life of affected individuals. The major forms of mood disorder include bipolar disorder (manic depression) and unipolar disorders (major depression and unipolar mania). Other mood disorders include dysthymic disorder, cyclothymic disorder, seasonal affective disorder and substance-induced mood disorder.
Bipolar disorder is a common condition with a lifetime prevalence of 1.2% to 1.6% (Weissman et al. 1988, Psych. Med. 18:141-153; Kessler et al. 1994, Arch. Gen. Psych. 51:8-19). It is characterised by recurrent episodes of mania and depression with symptomatic recovery between episodes.
The pathophysiology of bipolar disorder remains poorly understood despite considerable research (Goodwin et al. 1998, Arch. Gen. Psych. 55:23-25). Although it is strongly heritable, the genetics are complex, with less than full concordance in monozygotic twins (Mitchell et al. 1993, Aust. and New Zeal. J. Psych. 27:560-580). At least four different susceptibility loci have been identified (Adams et al. 1998, Am. J. Hum. Genet. 62:10841091). A trait-dependent biological marker would assist genetic linkage studies (which are dependent upon the identification of the clinical phenotype) and would potentially lead to an understanding of the underlying molecular defect in bipolar disorder.
In unipolar depression, there are recurrent episodes of depression with symptomatic recovery, but there are no episodes of mania. In unipolar mania there are recurrent episodes of mania but no episodes of depression. Like bipolar disorder, the pathophysiology and specific genetic defects underlying unipolar disorders remain poorly understood.
Current techniques for diagnosing mood disorders rely entirely on subjective interpretation of a patient""s condition based on clinical interview. However, apart from being relatively time-consuming, the subjective nature of this technique in interpreting a psychiatric profile does not provide consistently accurate determinations of clinical phenotype. Consequently, misdiagnosis of mood disorders may occur which can thereby affect the prescribed pharmacological and non-pharmacological therapy.
In the 1930s, Hunt and Guilford (1933, J. Abnormal and Social Psychology 28:443-452) found that hospitalised manic-depressive patients displayed slow alternation rates when viewing an ambiguous figure (ie. Wheatstone cube) compared to normal controls. The mean passive viewing number of alternations per minute was 4.25 for manic-depressives and 18.06 for normal controls. A strong implication from this study is that such slower alternation rates may be the result of clinical progression. Moreover, the data from this study support the use of this test to confirm the presence of manic-depressive illness in hospitalised individuals with a life history of illness at least as long as that for the individuals in the study.
The present invention arises from the unexpected discovery of differential rates of binocular rivalry between subjects with mood disorders (particularly unipolar and bipolar mood disorders), and non-clinical controls. In this respect, it was found that euthymic subjects affected by these mood disorders have a statistically significant slower rate of rivalry compared to non-clinical control. Surprisingly, the inventors also discovered that slow rates of binocular rivalry are present in some relatives of subjects with mood disorders. These findings suggest that slow binocular rivalry alternation rate is an alternative phenotypic expression of the bipolar and/or unipolar genotype and is not the result of one or more clinical episodes.
The inventors have also found from unilateral caloric, and transcranial magnetic, stimulation during binocular rivalry (as hereinafter described) that binocular rivalry is likely to be an interhemispheric switching phenomenon, ie. the perceptual alternations relate to alternating activation of the left and right hemispheres of the brain. Thus, the inventors consider that slow binocular rivalry is likely to correspond to slow rate of interhemispheric switching. The inventors have also shown that unilateral caloric stimulation also alters the perceptual alternations of the Necker cube, thus supporting interhemispheric switching as the neural mechanism of ambiguous figures. The similarly abnormal (slow) alternation rates in binocular rivalry and the Necker cube in subjects with bipolar disorder suggest that these perceptual phenomena share a common neural mechanism. The similar effects of caloric stimulation on binocular rivalry and Necker cube alternations suggest that this common neural mechanism is interhemispheric switching.
Accordingly, the inventors have devised a method of diagnosing mood disorders or predisposition therefor based on the above candidate trait-dependent biological marker. The current method therefore may also have utility in genetic linkage studies for the identification of the molecular defect(s) underlying these disorders, and for the identification of compounds which may alleviate such disorders. Other aspects of the invention will become apparent from the following description.
Thus, in one aspect, the invention broadly resides in a method for diagnosis of a mood disorder or predisposition therefor in a test subject, said method including the steps of:
(a) determining an interhemispheric switch rate of the test subject, wherein the test subject has not been diagnosed previously with the mood disorder; and
(b) comparing the switch rate with a corresponding reference switch rate to diagnose presence or absence of the mood disorder or predisposition therefor.
Suitably, the test subject has had less than two episodes of the disorder or is asymptomatic.
Preferably, the interhemispheric switch rate is determined by measuring a rate of perceptual rivalry in the test subject.
The rate of perceptual rivalry may be determined by measuring a rate of reversal of perspective for ambiguous optical stimuli.
Preferably, the rate of perceptual rivalry is determined by measuring a rate of binocular rivalry.
Alternatively, the interhemispheric switch rate may be determined by measuring a rate of the nasal cycle.
Suitably, the rate of perceptual rivalry is measured by:
(a) displaying at least one image to the test subject, wherein the at least one image invokes perceptual alternation;
(b) signalling respective incidences of perceptual alternation in the test subject during a predetermined period to provide a number of signals; and
(c) dividing the number of signals by the predetermined period to provide the rate of perceptual rivalry.
Preferably, the method is characterised in that said signalling is effected by the test subject or by a suitable detection means.
Preferably, the method is further characterised by the step of processing each of the signals relating to interhemispheric alternation to convert these signals into digitised signals, and storing the digitised signals for subsequent use.
Suitably, presence of the mood disorder is diagnosed, or a predisposition therefor is suggested, when the interhemispheric switch rate of the subject is equal to a corresponding reference switch rate associated with the mood disorder or predisposition therefor. In contrast, absence of the mood disorder may be diagnosed, or predisposition therefor discounted, if the above criteria are not satisfied and/or when the interhemispheric switch rate of the subject is equal to a corresponding reference switch rate associated with normal or control phenotype.
In the case of an interhemispheric switch rate determined by binocular rivalry, presence of bipolar disorder is diagnosed, or a predisposition therefor is suggested, preferably when the rate of perceptual alternation in the subject is less than 0.40 Hz, more preferably less than 0.35, and most preferably less than 0.30. Preferably, the stimulus for binocular rivalry is moving gratings.
Conversely, absence of bipolar disorder may be diagnosed, or a predisposition therefor discounted, when the rate of perceptual alternation is greater than 0.35 Hz, more preferably greater than 0.40 Hz, and most preferably greater than 0.45 Hz. Preferably, the stimulus for binocular rivalry is moving gratings.
Suitably, presence of unipolar disorder is diagnosed, or a predisposition therefor suggested, when the rate of perceptual alternation in the subject is in the range of between 0.25 Hz and 0.45 Hz. Preferably, the stimulus for binocular rivalry is moving gratings.
In another aspect, the invention provides a method for diagnosis of a mood disorder or predisposition therefor in a test subject, said method including the steps of:
(a) determining an interhemispheric switch rate of the test subject; and
(b) comparing the switch rate with a corresponding reference switch rate to diagnose presence or absence of the mood disorder or predisposition therefor; wherein the interhemispheric switch rate is not determined by reversal of perspective of ambiguous optical stimuli.
In yet another aspect of the invention, there is provided a method for diagnosis of a mood disorder in a test subject, said method including the steps of:
(a) determining binocular rivalry rate in the subject; and
(b) comparing said rivalry rate with a corresponding reference rivalry rate to diagnose presence or absence of the mood disorder or predisposition therefor.
In still yet another aspect, the invention provides a method for assessing the clinical state of a test subject with a mood disorder, said method including the step of comparing measurements of current relative hemispheric activation to corresponding measurements obtained when said subject was euthymic to thereby ascertain the clinical state.
Preferably, the relative hemisphere activation is measured by:
(a) recording binocular rivalry in the test subject;
(b) calculating a ratio of total time spent perceiving left eye""s presented image versus right eye""s presented image;
(c) determining which eye""s presented image is represented in which hemisphere; and
(d) interpreting which hemisphere has greater relative activation from the results of the aforementioned steps.
Suitably, the step of determining which eye""s presented image is represented in which hemisphere is carried out by the steps of:
(a) stimulating one of said hemispheres;
(b) calculating a post-stimulation ratio of total time spent perceiving left versus right eye""s presented image; and
(c) comparing pre- and post-stimulation ratios to determine whether left eye""s image or right eye""s image is represented in said stimulated or opposite hemisphere.
Suitably, said stimulation is effected by unilateral caloric vestibular and/or unilateral transcranial magnetic stimulation as, for example, hereinafter described.
In a further aspect of the invention, there is provided an apparatus for diagnosing mood disorder, said apparatus comprising:
(a) a monitoring means for monitoring interhemispheric switching in a test subject; and
(b) processing means for determining an interhemispheric switch rate and for comparing said switch rate with a predetermined data set for providing diagnosis of presence or absence of the mood disorder or predisposition therefor.
The monitoring means suitably comprises means for presenting different viewing images separately to each eye and recordal means for recording when the subject perceives a change in the viewed image.
Suitably the different viewing images comprise a moving horizontal grating presented to one eye and a moving vertical grating presented to the other eye. Alternatively, the different viewing images may be a stationary horizontal grating presented to one eye and a stationary vertical grating presented to the other eye.
The monitoring means preferably incorporates a liquid crystal shutter before each eye.
The recordal means for recording perceived change may suitably be a subjective device in the form of an indicator means activated by the test subject when a change is perceived.
Preferably, the recordal means is an objective device that records eye movements as an indicator of which image is being perceived. Alternatively, steady state visual evoked potentials may be measured to provide an objective indication of the perceptual alternation.
The processing means suitably includes timing means and means for receiving signals from the recordal means indicative of perceptual change.
The apparatus may also include change means for inducing a change in ratio of total time spent perceiving left eye""s presented image versus right eye""s presented image.
In yet a further aspect of the invention, there is provided a process for identifying one or more genetic markers associated with a mood disorder, said process including the steps of:
(a) testing respective members of one or more pedigrees affected by the mood disorder using the method of the invention;
(b) identifying members having the mood disorder or predisposition therefor; and
(c) conducting genetic linkage analysis on the identified members to identify the or each genetic marker associated with the mood disorder.
Preferably, the mood disorder is bipolar disorder or unipolar disorder.
In a still yet a further aspect, the invention provides a method of treating a patient with unipolar disorder, said method comprising the steps of:
(a) determining an interhemispheric switch rate of the patient;
(b) comparing said interhemispheric switch rate with a range of reference interhemispheric switch rates associated with bipolar disorder; and
(c) administering to said patient a pharmaccologically-effective dosage of a mood-stabilising drug when said interhemispheric switch rate is in said range.
Suitably, the mood stabilising drug is lithium.
Preferably, the interhemispheric switch rate is determined by perceptual alternation more preferably binocular rivalry. In the latter case, the drug is administered to the patient when the alternation rate is below 0.25 Hz, more preferably below 0.20 Hz, and most preferably below 0.15 Hz.